Association of the Charcot–Marie–Tooth disease gene ARHGEF10 with paclitaxel induced peripheral neuropathy in NCCTG N08CA (Alliance)

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Highlights

  • N08CA studied 138 patients undergoing neurotoxic paclitaxel chemotherapy.

  • Polyneuropathy phenotyped by serial patient reported outcomes using CIPN20.

  • Gene ARHGEF10 found to be associated with paclitaxel polyneuropathy.

  • Study validates result of previous report in the paclitaxel trial N08C1.

  • Toxic neuropathies such as from paclitaxel may have a genetic component.

Abstract

The predisposition of patients to develop polyneuropathy in response to toxic exposure may have a genetic basis. The previous study Alliance N08C1 found an association of the Charcot–Marie–Tooth disease (CMT) gene ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy (CIPN) related to the three non-synonymous, recurrent single nucleotide variants (SNV), whereby rs9657362 had the strongest effect, and rs2294039 and rs17683288 contributed only weakly.

In the present report, Alliance N08CA was chosen to attempt to replicate the above finding. N08CA was chosen because it is the methodologically most similar study (to N08C1) performed in the CIPN field to date. N08CA enrolled patients receiving the neurotoxic chemotherapy agent paclitaxel. Polyneuropathy was assessed by serial repeat administration of the previously validated patient reported outcome instrument CIPN20. A study-wide, Rasch type model was used to perform extreme phenotyping in n = 138 eligible patients from which “cases” and “controls” were selected for genetic analysis of SNV performed by TaqMan PCR.

A significant association of ARHGEF10 with CIPN was found under the pre-specified primary endpoint, with a significance level of p = 0.024. As in the original study, the strongest association of a single SNV was seen for rs9657362 (odds ratio = 3.56, p = 0.018). To further compare results across the new and the previous study, a statistical “classifier” was tested, which achieved a ROC area under the curve of 0.60 for N08CA and 0.66 for N08C1, demonstrating good agreement.

Retesting of the primary endpoint of N08C1 in the replication study N08CA validated the association of ARHGEF10 with CIPN.

Introduction

Polyneuropathies rank among the most common neurological disorders. In the majority of cases, polyneuropathy is conceptualized as an “acquired” disorder such as from chronic hyperglycemia in diabetics or from other toxic exposures. However, toxic exposure appears not to be deterministic, because only some exposed patients will develop neuropathy, while others may not. Genetic variability between individuals is a possible explanation raising the possibility that polyneuropathy susceptibility may in some patient populations be a complex genetic trait.

Charcot–Marie–Tooth (CMT) disease refers to a group of hereditary polyneuropathies that are monogenic with high penetrance. Approximately 80 genes have been conclusively identified as CMT genes [1], [2], [3], [4].

Genomic studies of complex traits may gain additional power from leveraging what is already known about mutations in genes that are responsible for Mendelian diseases [5], [6]. Recently, we reported a genetic discovery study on a toxic neuropathy by massively parallel (“nextgen”) sequencing of all CMT genes in 119 patients. Patients were part of the chemotherapy-induced peripheral neuropathy (CIPN) observational clinical trial Alliance N08C1. The lead finding of the study (under the pre-specified primary endpoint) was the association of the CMT gene ARHGEF10 with susceptibility to polyneuropathy. Three single nucleotide variants (SNV) contributed to the per-gene testing, rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect with an odds ratio of 4.8 and a significance level of p = 4 × 10 4 [7].

Replication in an independent patient cohort represents the gold standard for validating genetic associations. In the case of CIPN, such validation has not always been successful (e.g. Schneider et al., [8] was refuted by Bergmann et al., [9] and Kulkarni et al. [10]). A dominant reason for poor reproducibility among these studies may be related to the poor quality of neurological assessments of polyneuropathy reported in many studies performed in oncology. Oftentimes, polyneuropathy is only sporadically assessed by cancer care providers who are not well-trained in the subtleties of the assessment required. Accordingly, some authors concluded that these studies failed to provide reliable discrimination of who suffered from CIPN because a “phenotype of convenience” was used [11] instead of a prospectively implemented assessment of polyneuropathy with well-validated methods.

Our recent study N08C1 implemented a different approach to polyneuropathy phenotyping. We quantified the rate of progression of polyneuropathy over the study period as the “slope” of symptom progression. The rate (or slope) was derived from up to 12 weekly polyneuropathy assessments conducted while patients were exposed to repeat doses of neurotoxic chemotherapy. Polyneuropathy assessments were performed with a patient reported outcome (PRO) instrument, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (CIPN20). This instrument was developed and validated by neurologists for the assessment of peripheral neuropathy in cancer patients [12], [13], [14], [15]. The CIPN20 methodology was recently demonstrated to cross-validate well with expert neurological exams [15]. Considering the concerns in the field discussed above, we sought to validate our published findings in Alliance N08C1 in a similarly designed study replicating polyneuropathy phenotyping and patient selection as closely as possible.

Here we report testing of the ARHGEF10 gene single nucleotide variants (SNV) rs9657362, rs2294039, and rs17683288 in an independent cohort, the CIPN clinical study Alliance N08CA [7].

Section snippets

Patients

The North Central Cancer Treatment Group (NCCTG, now “Alliance”) study N08CA is a recently reported randomized controlled trial of glutathione for prevention of CIPN in patients with ovarian or lung cancer [16]. Patients in the study were at least 18 years old and had to have a life expectancy of greater than 6 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were excluded if they had been diagnosed with peripheral neuropathy (from any cause including

CIPN cases and controls

Patient selection for the present study is shown in a Consort diagram (Fig. 1). 138 patients were eligible based on the having received the same paclitaxel chemotherapy regimen and having a minimum of three serial CIPN symptom assessments available. Of these patients, 63 were “uncategorized” because they had slopes of symptom progression that were not significantly different from the group median. The slopes (and standard errors) for these patients is shown in Fig. 1 (left) depicting that error

Discussion

The present study was designed to allow independent validation of a recently published report on CIPN genetics [7]. The original study, Alliance N08C1, was the first in the field to integrate cutting-edge next generation sequencing and reliable CIPN phenotyping by serial PRO with the CIPN20 instrument. The study concluded that mutations in non-CMT alleles, i.e., SNV, in the CMT gene ARHGEF10 were associated with CIPN. The present study successfully replicated this observation in an independent

Conflict of interest statement

The authors have not declared any conflict of interest. None of the authors has a financial or personal relationship with a third party whose interests could be positively or negatively influenced by the article's content.

Acknowledgments

Research reported in this publication was supported by the National Institute Of Nursing Research (NINR) under Award Number R01NR015259 (to A.S.B.), by the National Cancer Institute (NCI) under Award Numbers U10CA180821, U10CA180882 and 1UG1CA189823 (to the Alliance for Clinical Trials in Oncology), and by the National Center for Advancing Translational Sciences (NCATS) under Award Number KL2TR 000136 (to Mayo Clinic). The content is solely the responsibility of the authors and does not

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